Chapter 41. Pharmacology of Intravenous Anesthetics

1. Propofol decreases cerebral metabolic rate for oxygen and cerebral blood flow. By causing vasoconstriction of central nervous system (CNS) blood vessels, propofol also significantly decreases intracranial pressure.

2. Propofol produces a dose-dependent decrease in ventilatory drive. It decreases tidal volume and minute ventilation and increases Paco2. The ventilatory depressant effect is exaggerated in patients with underlying chronic obstructive pulmonary disease (COPD).

3. Propofol decreases myocardial contractility, leading to a reduction in cardiac output. It reduces smooth muscle tone, causing vasodilation in both systemic arteries and veins. Propofol also blunts the barostatic reflex, resulting in a slower heart rate for a given decrease in blood pressure.

4. Coexisting factors, such as other medications (eg, benzodiazepines and/or opioids), advanced age, or presence of concurrent disease (eg, cardiac dysfunction, COPD, hypovolemia), can increase the hemodynamic effects of propofol and decrease the amount needed to produce unconsciousness. Patients with acquired tolerance because of chronic use of other CNS depressants, anticonvulsants, or alcohol may require higher doses of propofol to produce unconsciousness.

5. Propofol causes the lowest incidence of postoperative nausea and vomiting of any general anesthetic agent, injected or inhaled. Propofol also has intrinsic antiemetic activity and has been used successfully as an antiemetic.

6. Propofol often causes pain on injection, which can sometimes be severe. Placing a tourniquet proximal to the injection site and administering lidocaine is the most effective way to prevent this pain.

7. Propofol is a very short-acting intravenous anesthetic. It undergoes relatively little accumulation, even after long-duration infusions. Because of its rapid recovery characteristics, it is an extremely useful drug for maintaining general anesthesia.

8. Fospropofol is a new, water-soluble prodrug of propofol. The onset of the sedative effect is slow.

9. The CNS effects of thiopental are qualitatively similar to those of propofol. When thiopental is given before a planned decrease in global cerebral perfusion, the likelihood of CNS damage appears to be reduced.

10. The cardiac and pulmonary effects of thiopental are qualitatively similar to those of propofol. Thiopental generally causes a smaller decrease in blood pressure.

11. The CNS effects of etomidate are similar to those of thiopental and propofol.

12. Etomidate is notable for its lack of cardiovascular effects. Given by itself, it has little effect on systemic arterial or venous vascular tone or on cardiac contractility, and usually little change in blood pressure or heart rate occurs. Cardiovascular stability is generally preserved in persons with hypovolemia or cardiac dysfunction.

13. Etomidate inhibits the enzyme responsible for performing the 11β-hydroxylation reaction in cortisol synthesis. A single induction dose of 0.3 mg/kg inhibits cortisol synthesis and the normal response to adrenocorticotropic hormone for up to 12 hours. Infusions of several days' duration in ventilated intensive care unit patients were associated with increased mortality.

14. Sedative doses of midazolam cause patients to become sleepy and calmer and to have anterograde amnesia. The amnestic effects of midazolam are variable but usually short-lived, and they should not be relied on to prevent recall of intraoperative events.

15. Intramuscular administration of midazolam results in reliable absorption and little injection pain. Its oral bioavailability is only approximately 15%.

16. Midazolam is synergistic with opioids or alcohol in depressing ventilatory drive. Patients with COPD are more sensitive to its ventilatory depressant effects.

17. Flumazenil is a benzodiazepine antagonist with a very short duration of action. When given by itself to healthy volunteers, mild anxiety and symptoms resembling those that occur during a panic attack may occur. When given to patients chronically taking benzodiazepines, acute withdrawal, including seizures, may occur.

18. Ketamine produces dissociative anesthesia. Under ketamine anesthesia, a patient may move, vocalize, open eyes, and make ocular tracking movements. Depth of anesthesia is difficult to assess. Also, in subhypnotic doses, ketamine produces profound analgesia. Ketamine is often preceded by an antisialagogue such as glycopyrrolate to reduce the large amount of salivation it produces.

19. Ketamine usually causes sympathetic activation leading to an increase in blood pressure, heart rate, cardiac contractility, cardiac output, and vascular resistance. It has little effect on ventilatory drive in normal patients or in patients with COPD, and it produces bronchodilation. Protective airway reflexes are less likely to be ablated than with other intravenous anesthetics.

20. Intramuscular administration of ketamine results in reliable absorption and little injection pain.

21. Droperidol produces a neuroleptic state in which behavior is diminished and responses to stimuli are fewer, slower, and smaller in magnitude. At high doses, it can produce catatonia, although consciousness and memory are preserved.

22. At very low doses, droperidol is an excellent antiemetic. At much higher doses, the drug can prolong cardiac repolarization (increase QTc interval), and this is the basis for a precaution from the US Food and Drug Administration regarding its use.

23. Dexmedetomidine is an α2-adrenoceptor agonist that produces sedation without associated amnesia. Even at high doses, loss of consciousness may not occur.

For 90 years after the introduction of ether as a general anesthetic agent, almost all general anesthetics were administered via the inhalational route. That practice changed in 1935 following the description by Lundy1 of the use of thiopental. During World War II, intravenous cannulation for the administration of blood products and crystalloid solutions was common, and it was increasingly utilized by physicians specializing in anesthesiology. Thiopental was widely used during surgery for battlefield wounds, and it was soon recognized that intravenous anesthesia with thiopental required greater skill and was not as "forgiving" as general anesthesia with ether.2 Over the next 3 decades, induction by inhalation became less and less common (with the exception of pediatric anesthesia) while additional intravenous agents were introduced to compete with thiopental.

Thiopental is an excellent intravenous anesthetic, and its introduction revolutionized the practice of anesthesiology. Newer agents such as propofol have improved on thiopental and largely supplanted it in clinical practice. The characteristics of an "ideal" intravenous anesthetic agent are listed in Box 41-1. How each of the available intravenous anesthetics approaches this ideal is described in detail. The unique characteristics of the individual agents must be considered when choosing the best drug for a particular patient and a specific clinical setting.

Chemistry

Propofol is 2,6-diisopropylphenol, a simple derivative of phenol (Fig. 41-1 and Table 41-1). Propofol is an oil at room temperature and is essentially insoluble in water. Its initial formulation used a detergent called Cremophor, but this solubilizer was found to produce anaphylactoid reactions. Propofol subsequently was prepared as a 1% emulsion in Intralipid, a commonly used source of nutritional fat in patients receiving total parenteral nutrition. Intralipid contains 10% soybean oil, 2.25% glycerol, and 1.2% egg lecithin. The propofol emulsion readily supports bacterial growth, and the original formulation was associated with numerous cases of iatrogenic sepsis. Currently, all propofol formulations have a bacteriostatic agent added in low concentration to slow, but not prevent, bacterial growth. Depending on the manufacturer, the bacteriostatic agent is 0.005% ethylenediaminetetraacetic acid (EDTA), 0.025% metabisulfite, or 0.1% benzyl alcohol. Propofol undergoes dimerization and oxidation to a quinone when exposed to oxygen. These chemical reactions occur at a more rapid rate in the preparation containing metabisulfite.3 When the metabisulfite-containing propofol preparation is exposed to room air, it becomes visibly yellow after approximately 6 hours because of the presence of quinone. Whether this oxidation product affects safety or efficacy is unknown, but all opened vials and syringes containing propofol (irrespective of preservative) should routinely be discarded after 6 hours in order to reduce the risk of bacterial contamination.

Pharmacodynamics

Central Nervous System

Propofol is a rapid-acting hypnotic whose effects after brief administration are terminated by rapid redistribution (Table 41-5). It exerts its central nervous system (CNS) effects primarily via the GABAA receptor, a ligand-gated ion channel. The GABAA receptor is coupled to a chloride channel; as the GABA effect increases, the postsynaptic membrane becomes hyperpolarized, and thus GABA acts as an inhibitory neurotransmitter. Propofol binds to a unique binding site and increases chloride conductance in a concentration-dependent manner. Thus propofol potentiates the inhibitory effects of GABA.4 In vitro studies suggest that it also acts to inhibit glutamate action at N-methyl-d-aspartate (NMDA) receptors.5

In the CNS, neuronal activity is coupled to oxygen utilization and delivery as a result of autoregulation (Table 41-2). By decreasing neuronal activity, propofol decreases both CNS oxygen utilization, as measured by the cerebral metabolic rate of oxygen consumption (CMRo2), and cerebral blood flow (CBF). By causing vasoconstriction of CNS blood vessels and therefore a reduction in cerebral blood volume, propofol also significantly decreases intracranial pressure (ICP). Although it has not been studied as well as thiopental for its neuroprotective activity, propofol appears to produce a similar effect.6

Cerebral perfusion pressure (CPP) is estimated to be the difference between the mean arterial pressure (MAP) in the carotid arteries and the ICP or, if low, the venous pressure in the jugular veins. It is significantly affected by the position of the patient with respect to gravity (see Chapter 51). Propofol must be used cautiously in this setting because it causes more hypotension than thiopental (see Cardiovascular System) and therefore is more likely to reduce CPP and thus CBF.

Propofol is an anticonvulsant, and it has been used to terminate status epilepticus. It probably does not produce this effect in sedative doses.7 Although propofol shortens the duration of "therapeutic" seizure during electroconvulsive therapy (see Chapter 69), it still can be used in this setting.8

Propofol has pharmacodynamic effects that differ from those of thiopental in several ways. It does not produce hyperalgesia in sedative doses, and it is more likely to suppress movement responses to painful stimuli at concentrations achieved during routine administration. Unlike thiopental, sedative doses of propofol can produce significant amnesia.9 At sedative and hypnotic concentrations, propofol is much more effective in reducing airway responsiveness, and the incidence of cough or laryngospasm is greatly reduced. On the other hand, induction of anesthesia with propofol often causes myoclonic movements, an effect that is much less common with thiopental. Finally, even subhypnotic concentrations of propofol have a direct antiemetic effect (see Nausea and Vomiting). In this respect it is unlike any other intravenous anesthetic agent.

Respiratory System

Propofol produces a dose-dependent decrease in ventilatory drive, with a decreased tidal volume and minute ventilation and an increased Paco2 (Table 41-3). At the usual intravenous anesthetic induction dose of 1 to 3 mg/kg, most patients will become apneic for a few minutes. Accompanying this ventilatory depression is a decrease in protective airway reflexes. The ventilatory depressant effect of propofol is exaggerated in patients with underlying chronic obstructive pulmonary disease (COPD), and there is a synergistic effect between propofol and opioids in decreasing ventilatory drive.

Airway resistance after intubation is lower after induction with propofol than after thiopental.10 Some persons with reactive airway disease become bronchospastic when exposed to sulfites in the environment, such as those found naturally in certain wines. Reports on the bronchospastic effects of the metabisulfite-containing propofol preparation are conflicting, but any such effects, if they exist, appear to be sporadic and minor.

Cardiovascular System

Propofol causes a greater decrease in systemic blood pressure than does thiopental (Table 41-4).11 Although the 2 drugs have similar depressant effects on cardiac contractility, propofol causes a larger reduction in venous and arteriolar systemic vascular resistance, resulting in decreases of both preload and afterload. Contributing to the hypotensive effect of propofol is its action in blunting the barostatic reflex, resulting in a slower heart rate for a given decrease in blood pressure compared with thiopental.12 The decrease in blood pressure with propofol injection is exaggerated in older persons and those with preexisting cardiac dysfunction or hypovolemia, those given opioid or benzodiazepine premedication, or those receiving therapy with β-adrenergic blockers or vasodilators. Propofol does not alter the normal resting pulmonary vascular resistance in dogs; however, it potentiates the pulmonary vasoconstriction produced by phenylephrine.13

Nausea and Vomiting

Propofol causes the least incidence of postoperative nausea and vomiting of any general anesthetic agent, injected or inhaled.14 The use of propofol as a maintenance anesthetic is associated with a very low incidence of postoperative nausea and vomiting, perhaps because residual subhypnotic concentrations are antiemetic.15 In addition, propofol has intrinsic antiemetic activity and has been used successfully as an antiemetic.16 The mechanism of this effect is unknown, although it does not involve dopamine D2 receptors such as with droperidol or metoclopramide.17

Other Effects

Propofol decreases renal blood flow and causes increased secretion of antidiuretic hormone. Subhypnotic doses appear to be effective in reversing the itching produced by cholestasis or by epidural morphine.18 Propofol is safe to give to patients with all types of porphyria and for those with malignant hyperthermia.

Adverse Effects

Pain on Injection

Propofol often causes pain, sometimes severe, on injection. The importance of this problem to the anesthesia community is indicated by the fact that, in the 20 years since the introduction of propofol, hundreds of publications have addressed this adverse effect. No technique is universally reliable in preventing this adverse effect, and there is no general agreement on which technique is most recommended.

Mitigating the pain on injection of propofol has involved 3 general approaches: modifying the vehicle in which the propofol is contained, adding a drug to the propofol emulsion, or administering a drug before propofol injection.

There appears to be a correlation between the incidence and severity of pain and the free concentration of propofol in the aqueous phase of the emulsion. Modifications of the emulsion that increase the free propofol concentration (ie, decreasing the concentration of lecithin) are associated with increases in pain. Conversely, a modified emulsion product has been developed that uses a mixture of medium-chain and long-chain triglycerides instead of egg lecithin (Propofol Lipuro). It has a lower free concentration of propofol and causes less pain on injection.19 Although not available in the United States (as of 2010), it is widely used in Europe and Japan.

Free propofol may exert its painful effect by stimulating the kallikrein-kinin system, resulting in the generation of bradykinin, which stimulates intravascular nociceptors. Administration of nafamostat, an inhibitor of kallikrein, before propofol injection has significantly decreased the incidence and severity of pain.20

Clinicians desiring a simple and practical method for alleviating pain on injection have studied numerous medications either given before propofol or mixed with the propofol emulsion. A meta-analysis of the published studies concluded that injection of lidocaine with a proximal tourniquet in place provided the highest efficacy.21 The authors recommended that "IV lidocaine (0.5 mg/kg) should be given with a rubber tourniquet on the forearm, 30 to 120 seconds before the injection of propofol." This method was superior to mixing lidocaine with propofol, which itself was superior to giving lidocaine without a tourniquet before injecting the propofol.

Hypersensitivity Reactions

Propofol does not cause histamine release and is only very rarely associated with hypersensitivity reactions. Although components of the emulsion are derived from eggs and soybeans, the product contains no egg albumin or soy protein (the proteins to which hypersensitive persons are most likely to react). Persons allergic to egg albumin or soy protein have been given propofol safely.

Pharmacokinetics

Lipid Solubility

Propofol is one of the most lipid-soluble drugs used in medicine. Its oil/water partition coefficient of 4700 is almost 10-fold higher than that of thiopental. This high lipid solubility, coupled with the large fraction of cardiac output typically delivered to the brain, is responsible for the very rapid onset of effect, typically well under 1 minute, after intravenous administration (Table 41-5).

Protein Binding

Protein-bound propofol is unable to diffuse across the blood–brain barrier and produce a pharmacologic effect. Propofol is approximately 98% bound to plasma protein. In clinical situations in which the plasma concentration of protein is decreased, as in hepatic disease or hemorrhage that has been treated only with crystalloid solutions and/or packed red blood cells, the free fraction of propofol will be elevated compared with normal, and lower doses of propofol may be needed. Despite being an extensively bound drug, propofol has a high hepatic extraction ratio (Table 41-6). The total clearance of propofol is greater than hepatic blood flow, indicating that there is significant extrahepatic metabolism (see Metabolism and Elimination).22

Redistribution

The redistribution half-life of a drug, often abbreviated as t1/2α, is the time required for the central compartment concentration of the drug to decrease by 50% as the drug is distributed to peripheral compartment(s) (see Chapter 40). Propofol t½α is approximately 1 to 2 minutes, indicating that the effect of a typical bolus injection will be terminated within 3 to 4 half-lives or approximately 3 to 8 minutes (Table 41-5).23 This process of redistribution is the primary process by which the pharmacologic effect of propofol is terminated. Unless very large doses are given or a long infusion is given, the processes of metabolism and elimination are much less important in terminating the drug's effect.

Metabolism and Elimination

The terminal half-life of a drug, often abbreviated as t1/2β for medications fitting a 2-compartment model (see Chapter 40), is a function of the processes of both metabolism and elimination. Propofol t1/2β is approximately 4 to 6 hours, substantially less than the corresponding value for thiopental.23 The rapid plasma clearance and relatively slow transfer of propofol from peripheral tissues into the plasma help explain why the propofol concentration drops so much more rapidly than thiopental after termination of a continuous infusion (see Maintenance of Anesthesia).

Approximately 60% of administered propofol is para-hydroxylated and then conjugated with glucuronide or sulfate at 1 of the 2 hydroxyl groups.24 In persons with normal hepatic and renal function, approximately 60% of propofol metabolism occurs in the liver and approximately 40% occurs in the kidneys.22 The overall clearance of propofol is not reduced in patients with end-stage renal disease25 or with cirrhosis.26 Significant propofol metabolism occurs in the lungs of some animals, but kidney rather than pulmonary metabolism of propofol may be more important in humans.22

Factors Affecting Pharmacodynamics and Pharmacokinetics

Many factors may alter the pharmacodynamics and pharmacokinetics of propofol. Elderly patients require lower doses of propofol to produce unconsciousness. This altered response is due to both increased sensitivity of the brain to the drug's effect (pharmacodynamic alteration)27 as well as decreased protein binding and decreased clearance (pharmacokinetic alterations).28

The pharmacokinetics of propofol in persons with significant impairment of hepatic function is complex. Despite a significant increase in volume of distribution, the total clearance rate is preserved.26 Persons with cardiac dysfunction typically have an exaggerated hypotensive response to propofol, to a greater degree than with thiopental. In hypovolemic shock, a lower propofol dose is needed because a greater fraction of the cardiac output goes to the brain. The hypovolemic patient tolerates propofol-induced vasodilatation very poorly.

Clinical Use

Induction of Anesthesia

Propofol is currently the most commonly used intravenous induction agent. The characteristics of propofol as an induction agent are listed in Table 41-7. An induction dose of 1 to 3 mg/kg is often given to the typical healthy patient undergoing elective surgery, but there is enormous variability between patients in the amount actually required. Coexisting factors, such as previous premedication (eg, with benzodiazepines and/or opioids), advanced age, or presence of concurrent disease (eg, cardiac dysfunction, COPD, hypovolemia), will decrease the required dose of propofol. Conversely, patients with acquired tolerance because of chronic use of medications that exhibit cross-tolerance with propofol (eg, benzodiazepines, barbiturates, anticonvulsants, alcohol) may require higher doses of propofol to produce unconsciousness.

If there is concern about a possibly exaggerated response to propofol and a rapid sequence induction is not planned, it may be prudent to administer the induction dose slowly or in divided doses, treating the initial bolus as a "test dose" and waiting 1 to 2 minutes to evaluate the effects.

After administration of the induction dose, consciousness is typically lost within 30 seconds, although this time may be longer in persons with a slow circulation time because of cardiac dysfunction. Recovery of consciousness usually occurs within 3 to 8 minutes; however, some degree of cognitive impairment may persist for hours. The time to awakening from propofol is slightly faster than that with thiopental, and patients are able to achieve recovery "milestones" (voiding, ambulation) more rapidly. A portion of the rapid recovery may be due to propofol's relative freedom from "hangover" and its tendency to cause an elevation in mood. Emergence from propofol is often accompanied by a sense of well-being,29 and patients occasionally become euphoric. Occurrence of hallucinations and sexual fantasies during emergence also has been reported.

Maintenance of Anesthesia

General anesthesia can be maintained by either intermittent intravenous boluses or continuous intravenous infusion of propofol. After an induction bolus, infusion rates of 100 to 200 mcg/kg/min typically are used to maintain general anesthesia in healthy patients. If nitrous oxide and/or opioids are administered concurrently, a reduction in the required propofol infusion rate by one-third to one-half may be anticipated. To maintain a nearly constant blood (and brain) concentration of propofol during an infusion requires that the infusion rate be decreased as the infusion continues (see Target-Controlled Infusion). Autonomic signs are not reliable end points for determining the depth of hypnotic effect with propofol. Processed electroencephalograph (EEG) monitors, such as the bispectral index or patient state index, are correlated with the level of consciousness and facilitate titrating the infusion rate. Elderly patients and those with coexisting cardiopulmonary disease typically will require reduced infusion rates. Because of propofol's higher clearance compared with that of thiopental, it accumulates to a much lesser degree, and its recovery characteristics after an infusion, even of very long duration, permit it to be an extremely useful drug for maintaining general anesthesia.

The context-sensitive half-time (CSHT) describes the time required for the central compartment blood concentration to fall by half as a function of the duration of an infusion (of variable rate designed to maintain a constant blood concentration).30 The CSHTs for propofol after 1-, 2-, and 6-hour infusions are approximately 11, 16, and 34 minutes, respectively (Fig. 41-2). Thus a "rule of thumb" for the CSHT for propofol would be to take the value of 11 minutes for a 1-hour infusion and add to that 4 minutes for each additional hour of infusion duration; this linear relationship remains valid for infusions up to approximately 10 hours in duration. Remember that CSHT is not the same as time to clinical recovery, which depends on the actual concentrations achieved.

Sedation

Sedation during regional anesthesia or monitored anesthesia care can be achieved by the administration of intermittent boluses or a continuous infusion of 1 or more sedatives. Frequently an opioid is given to relieve the discomfort that may accompany a noxious procedure as well as decrease the required dose of the sedative. Intermittent bolus administration of rapid-acting hypnotics like propofol or thiopental is riskier than continuous infusion, because it is easier to overshoot and produce periods of unconsciousness that may be accompanied by diminished or absent airway reflexes.

Propofol is commonly used for procedural sedation as well as for longer-term sedation in the intensive care unit (ICU). If loss of consciousness is to be avoided (as is the goal for most cases of procedural sedation), a loading dose of 0.5 to 1 mg/kg is used, followed by an infusion of 25 to 75 mcg/kg/min. Lower infusion rates will be required in persons given benzodiazepines and/or opioids, in elderly patients, and in those with coexisting cardiopulmonary disease.

Propofol is routinely used in the ICU for long-term (ie, weeks) sedation of patients requiring mechanical ventilation. Even in this setting, its recovery characteristics permit rapid recovery. For example, a patient who is sedated (but not rendered unconscious) for 2 weeks will recover in approximately 3 hours.31 This property allows a patient to be awakened intermittently from relatively deep propofol sedation in order to perform neurologic examinations. Long-term infusion of propofol may result in a very large dose of lipid, and this has been associated with hypertriglyceridemia and pancreatitis.32 Logically, propofol should be administered cautiously in patients with preexisting pancreatitis or hyperlipidemia. Long-term administration (particularly in critically ill children) has also been linked to a rare and often fatal disorder termed propofol infusion syndrome. The pathophysiology has not been well characterized, but typical features include rhabdomyolysis, metabolic acidosis, and cardiac and renal failure.33

Target-Controlled Infusion

By using estimates of the pharmacokinetic parameters for propofol, it is possible to achieve and maintain a targeted blood (or "effect site") concentration using a computer-controlled infusion pump (see Chapter 43). Such a target-controlled infusion (TCI) pump, with the pharmacokinetic constants for propofol built in, is marketed as the Diprifusor in many countries (but not in the United States). The patient's age, body weight, and desired blood concentration are entered, and the pump delivers a propofol bolus followed by a variable-rate infusion. The rate is automatically adjusted to match predicted losses from distribution and elimination in order to maintain a constant propofol concentration. TCI pumps have been used successfully in closed-loop delivery systems with processed EEG signals as a control variable. For scientists interested in studying TCI, several public-domain computer programs are available that facilitate this process.34 Most modern infusion pumps have the ability to be controlled by a computer, so by connecting the pump to a portable computer and using one of the available programs, a TCI can be delivered. Despite more than a decade of routine clinical use in other parts of the world, it must be emphasized that TCI is still considered an experimental treatment in the United States.

Chemistry

Fospropofol is a water-soluble prodrug of propofol. It is metabolized by alkaline phosphatases in the liver to yield propofol, phosphate, and formaldehyde. A substantial fraction of the liberated propofol undergoes further metabolism to inactive products before reaching the systemic circulation. After the usual clinical doses of fospropofol, formaldehyde concentrations do not approach the toxic range. Fospropofol is supplied as a 3.5% isotonic aqueous solution with a pH between 8.2 and 9.0.35 The sedative/hypnotic effects of fospropofol are due it its active metabolite propofol.

Pharmacokinetics

Unlike propofol, fospropofol has a small volume of distribution (0.33 L/kg). Like propofol, it is highly bound to plasma albumin (98%). Unfortunately, at the time of this writing, the kinetic behavior of fospropofol cannot be accurately described; all of the publications describing its kinetic behavior have been retracted due to a problem with the collection and preservation of the blood samples obtained from the volunteers.36

Thus far, fospropofol has been studied after bolus administration and short (10 minutes) infusion. There is clearly a significant lag time after bolus injection until sedative or hypnotic effects occur. For example, after a sleep dose of fospropofol, given as a bolus, approximately 3 to 4 minutes will elapse until consciousness is lost.35

Clinical Use

Fospropofol is approved for procedural sedation. The recommended dose is 6.5 mg/kg administered as a bolus, followed by intermittent bolus doses of 1.5 mg/kg. The loading dose should be decreased in the elderly and in persons with significant comorbidities. Unlike propofol, fospropofol is not associated with pain at the injection site. Bolus administration does, however, commonly cause a burning or itching sensation in the groin and perineum.

Interestingly, in the United States fospropofol is a controlled substance (Schedule IV), whereas its active metabolite, propofol, is not.35

Although fospropofol has not yet been adequately studied during prolonged infusion, it may ultimately find utility as a sedative in the ICU. Because it does not contain the lipid emulsion of propofol preparations, adverse effects related to prolonged lipid infusion (eg, pancreatitis) are unlikely.

Chemistry

A large number of barbiturates have been introduced into clinical medicine, but only 2 remain in use as intravenous anesthetics: thiopental (a thiobarbiturate) and methohexital (an oxybarbiturate; Fig. 41-1 and Table 41-1). Both of these medications are practically insoluble in water; however, they are weak acids, and their sodium salts are freely soluble in water. Thiopental is no longer available in the United States.

The usual concentrations of the sodium salts used clinically are 2.5% thiopental and 1% methohexital. Thiopental is soluble at higher concentrations, but pain on injection is likely to occur. The 2.5% thiopental solution usually is painless when given intravenously. This solution is irritating to tissues if it extravasates because it has a pH between 10 and 11. If accidentally injected intra-arterially, vasospasm and thrombosis may occur that can lead to limb loss if not treated rapidly. Recommended treatments include intra-arterial injection of a vasodilator (eg, papaverine or nitroglycerin) and an anticoagulant (eg, heparin). The 1% methohexital solution is more likely to cause pain after intravenous injection; however, it is well tolerated after intramuscular injection and can be given via this route in a patient who does not have intravenous access. Methohexital is also hazardous if inadvertently injected intra-arterially.

Both thiopental and methohexital are supplied in powdered form and usually are reconstituted with sterile, preservative-free water (although normal saline can be used). Neither reconstituted solution is stable in the long term, and the manufacturer's package inserts state that they are stable at room temperature for 24 hours. Despite this conservative recommendation, thiopental has been shown to be both chemically stable and bacteriologically sterile for at least 1 week after reconstitution when refrigerated.37 Under refrigeration, methohexital remains chemically stable and microbiologically sterile for at least 6 weeks.38

Pharmacodynamics

Central Nervous System

Like propofol, thiopental has its primary neuronal action at the γ-aminobutyric acid (GABA)A receptor. Although barbiturates allosterically affect GABA binding (and vice versa), GABA is not necessary for barbiturate action on the channel.39

The barbiturates are classified as sedative–hypnotics; they produce dose-related depression of the CNS, ranging from mild sedation to unconsciousness. Thiopental or methohexital rapidly produces unconsciousness, and awakening will occur in minutes unless additional drugs are given. When administered in subhypnotic doses, barbiturates can sometimes produce disinhibition and "paradoxical" excitation. These drugs are not analgesics, and suppression of movement or hemodynamic responses to painful stimuli requires plasma concentrations in excess of those needed to cause unconsciousness. Like propofol, thiopental decreases ICP, CBF, and CMRo2. In some instances thiopental may exert a "neuroprotective" effect (see later) in which decreased oxygen delivery to the CNS (eg, during clamping of an intracranial artery) may be less likely to result in CNS damage because there has been a profound drug-induced decrease in oxygen utilization.

Because of its effects on CMRo2, CBF, and ICP, intravenous thiopental injection may produce beneficial effects in patients with intracranial space-occupying lesions or cerebral edema associated with a brain tumor, intracranial hemorrhage, or head trauma (Table 41-2). The effect of thiopental on CPP in the supine patient is unpredictable. Thiopental decreases mean arterial pressure in a dose-dependent manner (see Cardiovascular System); however, if CPP is low in a patient because of an elevated ICP, the overall effect of thiopental may be beneficial.40

The ability of thiopental to produce "neuroprotection" is both variable and controversial. When thiopental is given in advance of a planned reduction or interruption of cerebral perfusion, the likelihood or severity of subsequent CNS damage appears to be less.41 In contrast, when thiopental is given after the onset of cerebral ischemia, such as following a cardiac arrest, no apparent beneficial effect is seen.42 Protective efficacy appears to be superior when the size of the ischemic area is smaller and when the total duration of ischemia is shorter (see Chapter 85 for detailed considerations on this topic).

Thiopental produces a dose-dependent effect on the EEG (Fig. 41-3).43 At sedative doses or at doses associated with excitation or disinhibition ("stage 2" anesthesia), median EEG frequency increases because alpha waves (7-13 Hz) typical of the awake state change to beta waves (13-30 Hz). As the depth of hypnosis increases, there is a decrease in frequency and an increase in amplitude (power) of the EEG waves. Surgical anesthesia is associated with an EEG characterized by a predominance of delta waves (0.5-3.5 Hz). Increasing the dose of thiopental further leads to burst suppression (characterized by alternating periods of delta waves and electrical inactivity) and, finally, a completely isoelectric ("flat-line") EEG. An isoelectric or burst suppression EEG pattern is associated with a profound decrease in both CMRo2 and CBF, and this end point has been used to titrate the dose of thiopental for brain protection studies. Some studies suggest that alternative mechanisms (eg, decrease in amino acid–induced excitotoxicity) are more important than reducing cerebral metabolic rate.44

Thiopental is an excellent anticonvulsant. The typical intravenous anesthetic induction dose of 4 to 7 mg/kg usually is effective in rapidly terminating seizures. Refractory status epilepticus is often treated with repeated boluses or with continuous infusion of thiopental; such patients usually also require mechanical ventilatory support and may require infusion of vasopressors (see Cardiovascular System).

In contrast to thiopental, methohexital may cause abnormal spiking activity of the EEG and may elicit seizures in patients with a seizure disorder, especially in those with psychomotor epilepsy. For this reason, methohexital has long been used as the hypnotic agent to render patients unconscious for electroconvulsive therapy. Methohexital is also associated with abnormal motor activity during induction of general anesthesia, such as myoclonic jerks, muscle tremors, and hiccoughs.

Respiratory System

The respiratory effects of thiopental are very similar to those of propofol (Table 41-3). At the usual intravenous anesthetic induction dose of 4 to 7 mg/kg, most patients will become apneic for a few minutes. Accompanying this ventilatory depression is a decrease in protective airway reflexes, although overall responsiveness of the airway is increased. The incidence of coughing and laryngospasm during induction is higher with barbiturates than with most other sedative–hypnotics.

Thiopental produces an increase in the circulating concentration of histamine (see Hypersensitivity Reactions). The effect of histamine on the respiratory musculature is to cause constriction in the trachea and dilation in smaller airways. Typically no net alteration in bronchial resistance occurs.45

Cardiovascular System

Thiopental typically causes a transient, although significant, decrease in systemic blood pressure when it is administered to induce general anesthesia (Table 41-4).46 This decrease in blood pressure is exaggerated in persons with preexisting cardiac dysfunction or hypovolemia, those given opioid or benzodiazepine premedication, or those receiving therapy with β-adrenergic blockers or vasodilators. Thiopental-induced hypotension is more pronounced in older patients and when the drug is administered rapidly. Thiopental has a direct effect on the heart, decreasing contractility and leading to a decrease in cardiac output. It also has a direct effect on both systemic arteries and veins, causing vasodilatation. This vasodilatation results in decreased systemic arterial pressure as well as decreased venous return to the heart, the latter effect compounding the decrease in cardiac output and blood pressure. An equipotent dose of methohexital causes slightly less hypotensive effect than does thiopental. Thiopental increases the pulmonary vascular resistance in rat lung,47 although this effect may not be significant in humans.48

Adverse Effects

Hypersensitivity Reactions

In an anaphylactic reaction, there is IgE-mediated release of vasoactive and immune mediators from mast cells and basophils. An anaphylactoid reaction results when a drug directly causes the release of some of these mediators from mast cells or basophils. Anaphylaxis and other true immunologic reactions to barbiturates are extremely rare. They occasionally produce an anaphylactoid reaction by displacing vasoactive mediators from tissue mast cells or basophils. Thiopental injection increases the circulating concentration of histamine 3.5-fold, with the histamine concentration returning to baseline within 10 minutes.49 This effect contributes to the overall decrease in systemic vascular resistance produced by the drug. Anaphylactic or anaphylactoid reactions to thiopental are much less common than are perioperative reactions to latex exposure or injection of muscle relaxants and antibiotics.50

Porphyria

Barbiturates are the prototypical inducers of the hepatic microsomal enzyme system, including the cytochromes P450 (CYP) and the glucuronyl transferases. The rate of metabolism of some medications may be increased in the postoperative period if a patient is given thiopental for anesthesia induction, although this effect is rarely of clinical consequence. Thiopental is also an inducer of the enzyme δ-aminolevulinic acid (ALA) synthase, an enzyme that catalyzes the initial step in the biosynthesis of heme. Thiopental is absolutely contraindicated in persons with certain porphyrias (Fig. 41-4). In 3 of the clinically important porphyrias, there is a deficiency in a heme biosynthetic enzyme that follows ALA synthase in the pathway, and ALA, which is neurotoxic, then accumulates. These 3 porphyrias are acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria,51 and the enzyme deficiencies responsible for them are shown in Fig. 41-4. Each of these is transmitted as an autosomal-dominant trait, so affected individuals usually are heterozygotes with approximately half the normal amount of enzyme. Interestingly, a fourth variety, porphyria cutanea tarda, also due to a deficiency in a heme biosynthetic enzyme, is not a contraindication to use of a barbiturate.51 Anesthetic medications generally considered safe or unsafe in persons with porphyria are listed in Box 41-2.

Renal Effects

Thiopental decreases renal blood flow and increases the secretion of antidiuretic hormone. The actions act together to decrease urine output.

Other Effects

In comparison with propofol (see Propofol, Nausea and Vomiting), thiopental used for anesthesia induction results in a higher incidence of postoperative nausea and vomiting. In sedative (ie, subhypnotic) doses, thiopental causes hyperalgesia (ie, it decreases the threshold to pain).52 This effect (and thiopental's tendency to accumulate) makes it a poor choice for intraoperative sedation during regional anesthesia or monitored anesthesia care. Thiopental is safe to use in patients susceptible to malignant hyperthermia.

Pharmacokinetics

Lipid Solubility

Thiopental is administered as the alkaline (pH 10-11) solution of its sodium salt, but it is buffered to physiologic pH immediately upon contacting the circulation. Because its pKa is 7.5, at physiologic pH slightly more than 50% of the thiopental molecules are uncharged and therefore lipid soluble. Its oil/water partition coefficient of approximately 500 is more than twice that of halothane, indicating that it is highly lipid soluble. This high lipid solubility, coupled with the large fraction of the cardiac output typically delivered to the brain, is responsible for the very rapid onset of effect, typically well under 1 minute, after intravenous administration.

Protein Binding

Thiopental is approximately 85% bound to plasma protein. Protein-bound thiopental is unable to diffuse across the blood–brain barrier and produce a pharmacologic effect. In addition, the extensive binding of thiopental limits overall hepatic clearance, as only free drug is taken up by the liver to be metabolized. In clinical situations in which the plasma concentration of protein is decreased (eg, hepatic disease or hemodilution due to fluid resuscitation), the free fraction of thiopental is elevated, and lower doses of thiopental may be needed.

Redistribution

Thiopental has a redistribution half-life (t½α) of approximately 2 to 4 min,53 indicating that, after a typical bolus injection, the effect of the drug will be terminated within 3 to 4 half-lives or approximately 6 to 16 minutes (Table 41-5). Redistribution out of the CNS is the primary process by which the pharmacologic effects of thiopental are terminated. Unless the drug is given in very large doses (eg, barbiturate coma), in repeated doses, or by a long continuous infusion, metabolism and elimination are much less important in terminating its effect.

Metabolism and Elimination

Thiopental has a terminal half-life (t1/2β) of approximately 6 to 12 hours.53 Thiopental undergoes an interesting metabolic reaction catalyzed by CYP. The initial step is oxidation of the sulfur atom, forming a sulfoxide derivative that spontaneously rearranges, leaving oxygen in place of the sulfur in the barbiturate ring. This metabolite is the active barbiturate, pentobarbital. Because of slower redistribution, pentobarbital is a longer-acting drug than thiopental. Thus, when large cumulative doses of thiopental are given, clinically significant concentrations of pentobarbital occur. Pentobarbital contributes to the overall effect and makes thiopental appear as a much longer-acting medication.54 Other inactive hydroxylated metabolites of thiopental also are produced. Methohexital has a lower volume of distribution and a higher hepatic clearance than thiopental, and it is metabolized to inactive hydroxylated metabolites (Table 41-5).

Factors Affecting Pharmacodynamics and Pharmacokinetics

Many factors affect the pharmacodynamics and pharmacokinetics of thiopental. For example, elderly patients require lower doses of thiopental to produce unconsciousness. This altered response is due to the decreased rate of distribution from the central compartment to the rapidly equilibrating compartment.55

The pharmacokinetics of thiopental in persons with significant impairment of hepatic function is complex. The fraction of unbound thiopental is increased because of decreased plasma albumin concentrations, but hepatic clearance of unbound drug is decreased. Total clearance remains normal.53 Persons with cardiac dysfunction typically have an exaggerated hypotensive response to thiopental. In patients who are hypovolemic, a lower thiopental dose is needed because a greater fraction of the cardiac output goes to the brain. The hypovolemic patient may tolerate thiopental-induced vasodilatation very poorly.

Clinical Use

Induction of Anesthesia

The characteristics of thiopental as an induction agent are listed in Table 41-7. An induction dose of 4 to 7 mg/kg is reasonable in the typical healthy patient undergoing elective surgery. Coexisting factors, such as previous premedication (eg, with benzodiazepines and/or opioids), advanced age, or presence of concurrent disease (eg, cardiac dysfunction, COPD, hypovolemia) will decrease the required dose of thiopental. Patients with acquired tolerance because of chronic use of barbiturates or cross-tolerance to benzodiazepines, anticonvulsants, or alcohol may require higher doses of thiopental to produce unconsciousness.

If there is concern about a possibly exaggerated response to thiopental, a prudent practice would be to administer the induction dose slowly or in divided doses, using a small initial bolus as a "test dose" and waiting 1 to 2 minutes to evaluate the central nervous and hemodynamic responses.

After administration of the induction dose, consciousness typically is lost within 30 seconds, although this time may be longer in persons with a slow circulation time because of cardiac dysfunction. Recovery of consciousness usually occurs within 6 to 16 minutes; however, some degree of cognitive impairment (a "hangover") may persist for hours.

The induction dose of methohexital is 1 to 3 mg/kg. Onset and awakening are similar to those with thiopental; however, the duration of cognitive impairment will be somewhat shorter. As mentioned previously, excitatory effects like twitching and hiccoughs are often seen during induction.

Maintenance of Anesthesia

General anesthesia can be maintained by either intermittent intravenous boluses or a continuous intravenous infusion of thiopental; however, a rapid recovery should not be anticipated. Giving any rapidly redistributed medication by intermittent bolus results in a series of peaks and troughs in both blood concentration and effect, typically causing alternating periods of overmedication and undermedication. A continuous infusion, typically following a loading dose, permits a more constant blood (and brain) concentration and effect (see Chapter 43).

The CSHTs for thiopental after 1- and 2-hour infusions are approximately 80 and 100 minutes, respectively (Fig. 41-2). Thus thiopental is not a good choice for a maintenance infusion when rapid emergence and recovery are desired.

Methohexital has shorter CSHT values than does thiopental. The CSHTs for methohexital after 1- and 2-hour infusions are approximately 26 and 48 minutes, respectively (Fig. 41-2). Although shorter than for thiopental, emergence and recovery after an infusion of methohexital are still prolonged.

Sedation

Barbiturates are infrequently used for procedural sedation (except perhaps the use of methohexital during office-based oral surgical procedures). In subhypnotic doses, thiopental is less likely than propofol to produce anterograde amnesia9 (usually considered a desirable effect), and there may be hyperalgesia to pain.

Chemistry

Etomidate is an imidazole derivative whose structure is unlike that of any other anesthetic (Fig. 41-1 and Table 41-1). Its imidazole nucleus permits it to bind to, and inhibit, certain isozymes of CYP (see Endocrine Effects). It contains an ester linkage that is hydrolyzed to produce an inactive metabolite. With a pKa of 4.2, it is ionized and water soluble at acidic pH and lipid soluble at physiologic pH. It is supplied as a 0.2% solution in 35% propylene glycol.

Pharmacodynamics

Central Nervous System

Etomidate works via GABAA receptors to produce rapid onset of unconsciousness. It has a brief duration of effect, similar to that of thiopental and propofol. The drug has virtually no analgesic effects, so usually it must be combined with other drugs to suppress autonomic or somatic responses to painful surgical stimulation. Induction of anesthesia is frequently accompanied by myoclonic movements (Table 41-7). Such myoclonic movements may be substantially mitigated by the prior administration of a small dose of midazolam.56

Cardiovascular System

Etomidate is notable for its lack of cardiovascular effects, although the reasons for this remain obscure (Table 41-4).57,58 At the typical induction dose of 0.3 mg/kg, it has little effect on arterial or venous vascular tone or on cardiac contractility. After induction of general anesthesia with etomidate, usually little change in blood pressure or heart rate occurs. It must be emphasized that etomidate is almost never administered alone, and the addition of other drugs may substantially alter the cardiovascular effects. Cardiovascular stability usually is preserved in persons with hypovolemia or cardiac dysfunction. Etomidate does not release histamine. At the higher dose of 0.7 mg/kg needed to produce EEG burst suppression, hypotension due to vasodilatation has been reported.59

Respiratory System

Etomidate has less of a ventilatory depressant effect than does thiopental or propofol; however, an induction dose is still likely to result in transient apnea particularly when an opioid has also been administered (Table 41-3). The ventilatory depressant effect is not exaggerated in persons with COPD.

Endocrine Effects

In 1984, Watt and Ledingham60 reported a 2-fold increase in mortality among ventilated ICU patients who were given etomidate for 5 days or longer. This excess mortality subsequently was confirmed and attributed to the production of adrenal insufficiency. At clinically relevant concentrations, etomidate inhibits the mitochondrial CYP isozyme (CYP11B) responsible for catalyzing the 11β-hydroxylation reaction in cortisol synthesis. Etomidate is also able to inhibit the 17α-hydroxylase isozyme, although not at the plasma concentrations achieved during clinical infusions.61 The duration of suppression of cortisol synthesis by etomidate is dependent on the cumulative dose. A single induction dose of 0.3 mg/kg inhibits cortisol synthesis and the normal response to adrenocorticotropic hormone for up to 12 hours. However, the effects are not large, and there is no convincing evidence that this effect is deleterious in normal persons undergoing elective surgery. The clinical relevance of this effect remains controversial over 25 years after its description. Nevertheless, fear of adrenal suppression has significantly limited the popularity of etomidate over the years (see Clinical Use). Analogues of etomidate that do not inhibit cortisol synthesis are being investigated (see Future Horizons: Experimental Drugs).

In 2005, Jackson warned against the use of etomidate in patients with septic shock.62 Since then there have been several studies that have attempted to confirm or refute the safety of etomidate in critically ill patients, including those with sepsis. Unfortunately, these studies disagree: some confirm the danger of etomidate,63-66 whereas others support its continued use.67-71

Other Effects

Etomidate produces changes in CMRo2, CBF, and ICP similar to those seen with thiopental and propofol. In contrast, etomidate will not likely lower, and may actually increase, CPP because it has minimal effect on blood pressure while decreasing ICP. Etomidate may be useful in the short-term management of the neurosurgical patient in whom cardiovascular stability is desired.

Etomidate is associated with the highest incidence of postoperative nausea and vomiting among the intravenous anesthetics (30%-40%, by some estimates). The propylene glycol solvent can cause pain on injection and superficial phlebitis. Excitatory phenomena, such as hiccoughs and myoclonic movements, are common during induction. The safety of etomidate in patients with porphyria is questionable. Although a few case reports have described its safe use in patients known to have porphyria, etomidate induces the synthesis of ALA synthase in rats. Etomidate is safe to give patients with malignant hyperthermia.

Pharmacokinetics

After an induction dose of 0.3 mg/kg, loss of consciousness and recovery will be similarly rapid, as with thiopental and propofol. Because of the long duration of adrenal suppression associated with etomidate infusions, continuous administration has not been as extensively studied. Its redistribution half-life is similar to that of thiopental, whereas its terminal half-life is shorter than that of thiopental and similar to that of propofol (Table 41-5).

Etomidate is approximately 75% bound to plasma proteins, a fraction that is significant but not as high as for thiopental or propofol. Most of an administered dose of etomidate is metabolized via ester hydrolysis, yielding an inactive carboxylic acid that is excreted in the urine. Despite the presence of high concentrations of esterases throughout the body, hydrolysis of etomidate occurs primarily in the liver. It has a high extraction ratio of 0.7, so alterations in hepatic blood flow should affect clearance. Because the effects of a bolus are terminated by redistribution and repeated doses or infusions are unlikely to be given, hepatic clearance of etomidate is unlikely to play an important role in recovery (Table 41-6).

Clinical Use

Etomidate is a popular choice for induction of anesthesia in patients compromised by cardiac dysfunction or hypovolemia (Table 41-4). Hemodynamic stability after induction with etomidate is superior to that of any alternative method of induction. In theory, etomidate's pharmacokinetics should make it an excellent drug for use during short surgical procedures, but the high incidence of nausea and vomiting is a major disadvantage for patients undergoing same-day surgery. The occurrence of myoclonus and hiccoughs is annoying but similar in frequency to that seen with methohexital.

After more than 25 years of using etomidate, what can we conclude about the importance of adrenal suppression? When etomidate is used for induction and short-term maintenance, reduction in cortisol historically has not been a problem, although there is substantial conflict in the literature on this issue. As mentioned, a single induction dose of etomidate may be hazardous in patients with established or evolving septic shock. In contrast, a review concluded that there was no harm from etomidate infusions during coronary surgery and that the stress of a major operation overcomes the inhibition of cortisol synthesis.72 Some investigators have proposed the concurrent administration of etomidate plus a glucocorticoid, but in the absence of adequate studies, this routine practice cannot be recommended.

Ultimately, the decision to use etomidate must rest on the proven benefits of this drug, that is, cardiovascular and respiratory stability. These benefits are most likely to be seen when higher doses are used during induction. In our opinion, there is little compelling reason to use etomidate for maintenance of anesthesia or for procedural sedation.

Chemistry

Three injectable benzodiazepines are used in the perioperative period: midazolam, diazepam, and lorazepam (Fig. 41-1 and Table 41-1). Diazepam and lorazepam are "classic" benzodiazepines that are lipid soluble and difficult to solubilize for injection. Diazepam injection is supplied as a 0.5% solution in 40% propylene glycol and 10% ethanol. Lorazepam is supplied as a 0.4% solution in 80% propylene glycol, 18% polyethylene glycol, and 2% benzyl alcohol. Midazolam has unique properties as a result of its substituted imidazole ring. The imidazole nitrogen has a pKa of 6.2, so it becomes protonated and water soluble when buffered in a solution of pH 3 to 4 (as supplied in the vial).73 At physiologic pH, more than 90% of the midazolam molecules exist in the unprotonated lipid-soluble form. Hydroxylation of the methyl group on this imidazole ring decreases the pharmacologic activity of midazolam and increases its clearance, permitting this drug to be shorter acting than the other injectable benzodiazepines.

The water solubility of midazolam at low pH has erroneously been attributed to opening of one of the rings in the benzodiazepine nucleus. In fact, all benzodiazepines undergo ring opening at low pH. At pH 2, 75% of the midazolam molecules are in the open-ring configuration, whereas at pH 4, that percentage decreases to 9%.61 Because midazolam is supplied at a pH of 3 to 4 in the vial, ring opening can account for only a small percentage of its water solubility at that pH.

Pharmacodynamics

Central Nervous System

Benzodiazepines bind to a specific site located at the interface between the α- and γ-subunits of the pentameric GABAA receptor. GABA itself appears to bind at a different site between the α- and β-subunits.39 Unlike the relatively nonselective barbiturates or propofol, the benzodiazepines bind preferentially to GABAA receptors containing α1,2,3,5 and γ-subunits. Binding by endogenous benzodiazepine ligands (endozepines) or by benzodiazepine agonists to this benzodiazepine receptor acts allosterically to increase the affinity of the GABA receptor for GABA. Thus benzodiazepines potentiate the inhibitory effects of GABA, thereby increasing chloride conductance and hyperpolarizing neuronal membranes. Unlike barbiturates, benzodiazepines have a much more limited effect on neuronal hyperpolarization. The limited effect and selective CNS binding probably account for the great safety of benzodiazepines; they lack significant toxicity, even when they are taken in very high doses. At higher doses, such as those necessary to produce hypnosis or anticonvulsant effects, benzodiazepines may be working by non-GABA mechanisms such as inhibition of adenosine reuptake74 or inhibition of neuronal Ca2+ currents.75 Benzodiazepines also have agonist activity at the glycine receptor, an important inhibitory neurotransmitter in the spinal cord. Some of the effects of benzodiazepines, such as muscle relaxation, likely are mediated by their actions in the spinal cord. Benzodiazepine receptors in the periphery appear to regulate the initial step in the synthesis of steroid hormones from cholesterol.76 The physiologic significance of this action remains unclear.

Patients who are chronically taking benzodiazepines can become tolerant to some, but not all, of the effects. The initial drowsiness usually decreases, although some degree of psychomotor impairment seems to persist. Tolerance develops to the muscle relaxant and anticonvulsant effects, and the latter has limited the use of benzodiazepines in chronic seizure disorders. Alcohol, barbiturates, and benzodiazepines exhibit some cross-tolerance, so higher doses of these sedatives will be needed in patients with significant alcohol or barbiturate intake.

Benzodiazepines have effects on CMRo2 and ICP qualitatively similar to the effects of propofol; however, the magnitude of these effects is far less (Table 41-2). The effect of benzodiazepines on CBF and CPP is variable and is more of a function of their effects on blood pressure. Benzodiazepines are excellent anticonvulsants, although their primary use is limited to initial control of seizures and not prophylaxis. All of them raise the threshold for seizures induced by local anesthetics. Unlike thiopental and propofol, benzodiazepines, even in very high doses, do not cause burst suppression on the EEG or an isoelectric tracing, and they are not used for neuroprotection. Benzodiazepines given in subhypnotic doses produce amnesia for events after drug administration (anterograde amnesia).

Benzodiazepines are classified as "anxiolytics" because they are active in various animal models thought to represent anxiety. In patients who have chronic anxiety states, benzodiazepines can reduce anxiety at doses that are not highly sedating. Of note, the same effects may not occur in surgical patients. Many patients scheduled for surgery do not have high levels of self-rated anxiety, and the effect of midazolam is more likely to produce dizziness or sleepiness.77 An occasional patient may find the feeling of drunkenness or dizziness to be unpleasant.

Other Effects

Benzodiazepines produce much smaller cardiovascular effects than do thiopental or propofol, even when used for general anesthesia induction (Table 41-4). Some dilation of capacitance vessels leads to a decrease in venous return; however, there is little or no effect on myocardial contractility. Thus the overall effect on blood pressure and heart rate will depend on the volume status of the patient. Elevated blood pressure in the anxious patient is often lowered by low doses of benzodiazepines by virtue of their sedative properties (see later, Clinical Use).

Although benzodiazepines cause a dose-dependent decrease in hypoxic ventilatory drive, subhypnotic doses given alone rarely cause apnea. Doses of midazolam sufficient to induce unconsciousness produce apnea with a frequency similar to that of thiopental.78 There is profound synergy in depressing ventilatory drive between benzodiazepines and opioids or ethanol. Patients with COPD are more sensitive to the ventilatory depressant effects of benzodiazepines (Table 41-3).

Benzodiazepines, given alone, have a very low risk for causing nausea and vomiting. They are safe in patients with malignant hyperthermia, but they should be used with caution in persons with acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria because some benzodiazepines induce ALA synthase in rats. Hypersensitivity reactions to benzodiazepines are rare.

Pharmacokinetics

After an induction dose of 0.3 mg/kg midazolam, loss of consciousness is rapid; however, awakening will be much slower and hangover more prolonged than after thiopental or propofol. Simultaneous pharmacokinetic–pharmacodynamic modeling using an EEG end point suggests that midazolam is slightly slower in onset than is diazepam. The half-time to achieve steady-state effect was over 4 minutes, compared with 90 seconds for diazepam.79 The t1/2α for midazolam is 7 to 15 minutes, much longer than the 2- to 4-minute values for thiopental or propofol. The t1/2β for midazolam is 2 to 4 hours. When given by infusion, recovery after termination of a midazolam infusion will be longer than after propofol but shorter than after thiopental (Table 41-5).

Midazolam is metabolized primarily via hydroxylation of the N-methyl group on the imidazole ring. Although this metabolite has some residual benzodiazepine activity, circulating concentrations are low because midazolam is rapidly conjugated with glucuronic acid, yielding an inactive and rapidly excreted metabolite. Midazolam has high first-pass metabolism after oral administration, with an oral bioavailability of approximately 15%.80

Diazepam and lorazepam are metabolized and eliminated much more slowly than midazolam because of a high degree of protein binding (98%) and a much lower hepatic clearance. Whereas lorazepam is metabolized to an inactive glucuronide, diazepam is metabolized to several active metabolites. The most important of these active metabolites is nordazepam, which has an extremely long terminal half-life (100 hours vs 20 hours for diazepam). The processes of metabolism and elimination of these medications become important only when repeated doses or long infusions are given.

Clinical Use

Midazolam is the most commonly used preoperative sedative in anesthesia. It replaced diazepam largely because it does not produce pain on injection. Given as a single intravenous bolus, the effects of diazepam and midazolam are quite similar and have about the same duration. Lorazepam is slower in onset and longer in duration, and its tendency to cause prolonged amnesia may be undesirable for patients undergoing short procedures. After administration of 1 to 2 mg of midazolam, most patients become sleepy and calmer and have anterograde amnesia, effects that persist for 30 to 60 minutes. At these doses and in the absence of other medications, there are few significant effects on cardiorespiratory parameters. Sedation can be maintained by repeating intermittent boluses of 0.5 to 1 mg or by giving a continuous infusion. As with barbiturates, administration of benzodiazepines can sometimes produce paradoxical excitation.

The amnestic effects of benzodiazepines are dose related and often occur in patients who remain conscious and capable of normal conversation. The amnestic effects of midazolam (when given in usual doses for premedication) are variable but usually short lived, and they should not be relied on to prevent recall of intraoperative events. Although lorazepam has a shorter plasma half-life than does diazepam, its amnestic effects are more prolonged. This may be a function of higher affinity for benzodiazepine receptors.

Midazolam is commonly given by mouth for preoperative sedation in pediatric patients. The usual dose is 0.5 to 0.75 mg/kg, and a significant effect is apparent within 15 to 30 minutes. However, the peak effect may occur up to 1 hour after oral administration, so there might be significant postoperative sedation after short procedures.80 An official oral preparation of midazolam is unavailable in many countries. The intravenous solution can be mixed with fruit juice or flavored syrup; however, there is no completely effective way to mask the bitter taste.

Midazolam is 1 of only 2 induction agents (the other being ketamine) whose administration by the intramuscular route is well tolerated without pain and whose absorption is both reliable and predictable. Doses ranging from those that produce mild sedation up to those required to induce general anesthesia can be given intramuscularly. Doses in excess of a few milligrams should be given using the more concentrated 10 mg/mL preparation to minimize injected volume.

Diazepam is an excellent oral preoperative sedative and anxiolytic agent for patients undergoing inpatient surgery. A dose of 10 to 20 mg in an adult, or 0.2 to 0.4 mg/kg in a child, given by mouth an hour before transport to the operating room usually results in a drowsy and calm patient. Both diazepam and lorazepam are associated with significant pain when given intravenously, and the propylene glycol solvent can cause superficial phlebitis. Both medications are absorbed erratically when administered by intramuscular injection.

Midazolam can be used in higher intravenous doses (0.05-0.15 mg/kg) to induce anesthesia, or it can be given via continuous infusion during maintenance (see Chapter 42). The slower onset and offset of effect compared with propofol or thiopental are counterbalanced by midazolam's modest cardiovascular effects. The drug is not an analgesic, so it is usually administered with opioids. This significantly reduces the required dose of midazolam but usually causes a greater decrease in peripheral vascular resistance than seen with the individual drugs. This vasodilatation may be due to an increased effect on central sympathetic tone or possibly to a decrease in plasma catecholamines.81,82

The doses of midazolam and diazepam should be reduced in the elderly because of their increased sensitivity and reduced clearance. Hepatic disease or drugs that inhibit the oxidative metabolism of diazepam (eg, cimetidine) can significantly increase the intensity and duration of sedation.83 Because the hepatic clearance of midazolam is moderately high, elimination is not greatly affected by enzyme induction or inhibition. Renal disease, on the other hand, can delay the excretion of hydroxymidazolam and cause an increase in effect. Lorazepam is glucuronidated and has no active metabolites, so its effects are not markedly altered by moderate hepatic or renal disease.

Flumazenil

Flumazenil (Fig. 41-1) is a benzodiazepine antagonist.84 It has high affinity for the benzodiazepine binding site on the GABAA receptor, which prevents or reverses the effects of benzodiazepines and endozepines. There is no evidence that flumazenil will reverse nonbenzodiazepine CNS depression. The usual initial dose in a patient who has been given a therapeutic dose of a benzodiazepine is 0.1 to 0.2 mg intravenously. The initial dose can be repeated every 1 or 2 minutes up to a total dose of 1 mg to antagonize benzodiazepine-induced sedation. The various actions of benzodiazepines require different concentrations of agonist, and effects that require high doses (eg, hypnosis) are most sensitive to flumazenil reversal. Some effects, such as depression of hypoxic ventilatory drive, appear to be incompletely antagonized (see bulleted list that follows, second bullet).85

Reports that flumazenil is a weak partial agonist or inverse agonist are inconsistent. Healthy volunteers given a relatively high dose (2 mg) of flumazenil alone experienced mild anxiety and symptoms resembling those that occur during a panic attack.86 These symptoms are more likely to occur in patients with previously diagnosed panic attacks. These effects may indicate tonic activity in some critical GABAA pathways, and flumazenil may be acting weakly as an inverse agonist (ie, producing an effect opposite to that of the benzodiazepine). This action likely is not clinically important in the typical anesthesia setting in which flumazenil is used to reverse midazolam. Persons on chronic benzodiazepine therapy who are given flumazenil have been reported sporadically to have seizures,87 sometimes progressing to status epilepticus.88 This finding suggests that some patients develop physical dependence on the benzodiazepine, and flumazenil can precipitate withdrawal. A few cases of flumazenil-induced seizures in persons not on chronic drug therapy have been reported.87

Flumazenil is rapidly cleared by hepatic metabolism, with a half-life of approximately 1 hour. Therefore, it has a shorter duration than the benzodiazepines that are used to antagonize, so repeated doses usually are necessary.

The appropriate clinical roles for flumazenil are relatively limited:

• If a patient receiving midazolam for sedation becomes disoriented or uncooperative, reversal may be helpful. In contrast, planned use of flumazenil, that is, giving excessive amounts of benzodiazepines for a procedure and then relying on reversal at the end, will produce risk with little benefit. Such treatment risks ventilatory depression and loss of airway reflexes during the procedure and recurrence of depressant effects when reversal by the short-acting antagonist decays.
• Excessive sedation and ventilatory depression most often occur when benzodiazepines are combined with opioids. Flumazenil only partially reverses the depression of hypoxic ventilatory drive produced by midazolam, and it has no effect on ventilatory depression due to an opioid. In this setting, support of ventilation and administration of naloxone are more appropriate treatments.
• When flumazenil has been used empirically for treatment of suspected drug overdoses, deaths due to status epilepticus have occurred. Risk factors in such deaths include concurrent ingestion of tricyclic antidepressants and prior long-term therapy with benzodiazepines or anticonvulsants. Unless an overdose is known to be due to the acute ingestion of only a benzodiazepine, flumazenil treatment may be riskier than simply supporting blood pressure and ventilation until the drug effects wear off.

Chemistry

Ketamine is a derivative of aminocyclohexanone whose chemical structure is related to phencyclidine (Fig. 41-1 and Table 41-1). It is a weak base with a pK of 7.5 and is supplied in solution as the hydrochloride salt. The 3 concentrations available—10 mg/mL, 50 mg/mL, and 100 mg/mL—are typically used for monitored anesthesia care, intravenous anesthesia, and intramuscular injection, respectively. Ketamine is compatible in solution with atropine or glycopyrrolate, with which it is often mixed.

The commercial preparations of ketamine contain a racemic mixture of its 2 isomers. The S-isomer is a more potent anesthetic with fewer adverse effects,89 which is available in Europe, but not the United States.

Pharmacodynamics

Central Nervous System

Whereas all the previously discussed intravenous anesthetics potentiate the inhibitory effects of GABA, ketamine produces its inhibitory effects by blocking the NMDA receptor.90 The NMDA receptor is, like GABAA, a ligand-gated ion channel, but it is gated by the excitatory neurotransmitter glutamate. When open, it passes a current carried by calcium ions.

The anesthetic state induced by ketamine is called dissociative anesthesia. It does not resemble normal sleep; rather, patients appear to be dissociated from their environment. Under ketamine anesthesia, patients may move, vocalize, have their eyes open, and make ocular tracking movements. However, patients are anesthetized and do not respond to noxious stimuli or have any recall of events that occurred during the anesthetic. Ketamine causes profound analgesia that persists well into the postoperative period. Vivid dreams or hallucinations that may be perceived as unpleasant often accompany ketamine anesthesia, and hallucinations and/or dysphoria may occur in the postoperative period.

In contrast to the other intravenous anesthetics, ketamine produces increases in CMRo2, CBF, and ICP. Thus ketamine is relatively contraindicated in patients with an intracranial mass or increased ICP or who have suffered recent head trauma (Table 41-2).

Ketamine produces dose-dependent changes in the EEG that are quite different from those resulting from thiopental or propofol (Fig. 41-5).91 For this reason, EEG-based monitors of the depth of anesthesia (see Chapter 33) are not accurate when ketamine is the primary anesthetic. As seen with thiopental, light anesthesia with ketamine is associated with an increase in EEG frequency so that beta waves predominate. As the depth of anesthesia increases, high-amplitude theta waves, with intermittent delta waves, can occur. An isoelectric EEG does not occur with ketamine anesthesia.92

Cardiovascular System

In contrast to the other intravenous anesthetics, ketamine usually causes an increase in blood pressure, heart rate, cardiac contractility, cardiac output, and systemic vascular resistance (Table 41-4). These are indirect effects by virtue of increased centrally mediated sympathetic tone and increased centrally mediated release of catecholamines from the adrenal medulla. In the critically ill or injured patient whose circulating catecholamine concentration has reached its maximum value, ketamine may cause a decrease in blood pressure and cardiac output because the drug and its major metabolite have a direct negative inotropic effect. Ketamine may increase myocardial oxygen demand more than it increases oxygen delivery, and in some patients with coronary artery disease, this effect may lead to ischemia.

Respiratory System

Ketamine differs from the other intravenous anesthetics in its respiratory effects (Table 41-3). Ketamine has little effect on ventilatory drive in normal patients or in those with COPD. It produces bronchodilation and has proved useful in patients with, or prone to, bronchospasm. Protective airway reflexes are less likely to be ablated by ketamine, even in the presence of surgical anesthesia, although aspiration remains a risk. Ketamine causes copious salivation, and for this reason it is usually administered with an antisialagogue (eg, an anticholinergic drug such as glycopyrrolate).

Other Effects

Like etomidate, ketamine is associated with a high risk for postoperative nausea and vomiting. Ketamine is safe in patients with malignant hyperthermia and, based on a number of case reports, probably is safe in patients with porphyria.

Pharmacokinetics

After an intravenous induction dose of 1 to 2 mg/kg of ketamine, loss of consciousness is rapid; however, awakening will be much slower and the hangover more prolonged than after any other intravenous anesthetic. Ketamine has a redistribution half-life t1/2α of 11 to 17 minutes, much longer than the values for either thiopental or propofol (Table 41-5).

Ketamine is extensively metabolized, primarily by N-demethylation. The resulting active metabolite, norketamine, is approximately one-fourth as potent. Norketamine is further metabolized to an inactive glucuronide.

In contrast to the other intravenous anesthetics, only a small fraction of circulating ketamine is bound to plasma protein. Ketamine has a high hepatic extraction ratio, and other medications or coexisting diseases that decrease hepatic blood flow would be expected to prolong its duration of action (Table 41-6). Ketamine has high first-pass hepatic metabolism after oral administration, although it is sometimes administered by this route.

Clinical Use

Like etomidate, ketamine is most commonly used for induction of general anesthesia in patients compromised by concurrent cardiac dysfunction or hypovolemia (Table 41-4). It has been used extensively for acute and chronic treatment of burn victims. Infusions are used for analgesia and hypnosis as part of balanced anesthesia. Because increasing doses of ketamine do not produce consistent changes in hemodynamics, respiration, eye signs, or movement, the depth of anesthesia may be difficult to assess. Unless there is maximal sympathetic tone, ketamine usually causes an increase or no change in blood pressure. Ketamine is a good choice for patients with, or prone to, bronchospasm. A slow emergence, often accompanied by hallucinations and/or dysphoria, is a common adverse effect that must be balanced against the desire for a lack of cardiovascular depression. The unpleasant psychological effects may be mitigated, but not completely eliminated, by concurrent administration of propofol or a benzodiazepine.

In subhypnotic doses (0.15-0.3 mg/kg), ketamine is commonly used for monitored anesthesia care. It produces profound analgesia without the concurrent ventilatory depression produced by opioids. In combination with a low dose of propofol or a benzodiazepine, the unpleasant psychological effects are minimal, and the ventilatory depressant effects are much less than the combination with an opioid.

Ketamine is commonly used, either alone or in combination with midazolam, as an oral medication in children, especially as the sole agents for conscious sedation for a short but noxious procedure (eg, upper endoscopy). Typical doses of the combination are 3 to 6 mg/kg of ketamine plus 0.25 to 0.5 mg/kg of midazolam.

Ketamine is 1 of only 2 induction agents (the other being midazolam) that have reliable and predictable absorption with minimal pain after intramuscular injection. Doses ranging from those that produce mild sedation to those required to induce general anesthesia may be given intramuscularly. The preparation containing 100 mg/mL usually is given, especially in adults, to minimize the injected volume. A rapid onset after intramuscular injection makes ketamine a frequent choice for induction of anesthesia in children and adults with mental disabilities who will not tolerate a mask or the placement of an intravenous catheter. After intramuscular administration of 2 to 4 mg/kg of ketamine, the patient will lose consciousness, thus allowing placement of an intravenous catheter within approximately 5 minutes.

Butyrophenones

Droperidol and the closely related antipsychotic agent haloperidol exert their CNS effects via antagonism of the dopamine D2 receptor. Unlike their predecessors, the phenothiazines, they have less affinity at other sites, such as α-adrenoceptors or muscarinic cholinergic receptors. They are classified as neuroleptic agents because of their distinct behavioral effects. When a neuroleptic agent is given to a "normal" individual, behavior is diminished and responses to stimuli are fewer, slower, and smaller in magnitude. In high doses, a catatonic state is induced, although consciousness and memory are preserved. These drugs should generally not be given by themselves. Patients treated this way usually appear sleepy and comfortable when drug concentrations are maximal, but they often describe an intensely dysphoric experience after the effects have worn off. This is in distinct contrast to the benzodiazepines, which often produce anterograde amnesia. When a neuroleptic agent is given to a psychotic patient, the thought disorder usually improves. In schizophrenia, the delusions and auditory or visual hallucinations become less pronounced or disappear, and thinking becomes more orderly. Even if some hallucinations remain, the patient is far more likely to recognize them as unreal.

Droperidol is a highly effective antiemetic at doses (0.625-1.25 mg) that do not cause sedation or dysphoria. In rare instances, it may be useful in higher doses for its neuroleptic effect. Droperidol is a very safe sedative, albeit one often associated with dysphoria. It causes no ventilatory depression and, in contrast to the benzodiazepines, does not potentiate the ventilatory depressant effects of opioids.93 It has few cardiovascular side effects other than very mild vasodilatation due to its weak interaction with α-adrenoceptors. Butyrophenones can lower the seizure threshold and cause extrapyramidal symptoms (see next paragraph), so they are generally avoided in patients with seizure disorders or Parkinson disease. Many clinicians find droperidol useful for sedation during monitored anesthesia care or regional anesthesia in patients with dementia, psychosis, or mental retardation. In addition, droperidol may be useful to facilitate procedures such as line placement or awake intubation in uncooperative and/or intoxicated trauma patients. In such cases, its overall safety renders the possible later dysphoria a tolerable adverse effect.

Like all dopamine antagonists, droperidol has the potential to cause extrapyramidal reactions. These may include involuntary facial grimacing, neck stiffness, and limb movements such as akathisia ("restless legs"). These effects usually are not seen with antiemetic doses unless they are repeated, and they can be treated by administration of diphenhydramine or trihexyphenidyl, drugs with central anticholinergic effects.

An anesthetic technique rarely used today is neuroleptanesthesia, which involves the concurrent administration of droperidol, fentanyl (an opioid), and nitrous oxide. Anesthesia induction is accomplished via administration of 10 to 15 mg of droperidol and 250 to 500 mcg of fentanyl. Loss of consciousness and a lack of awareness are unlikely unless a high concentration of nitrous oxide is also given, and even then awareness still may occasionally occur. The neuroleptanesthetic state is accompanied by cardiovascular stability, and for this reason the technique gained some popularity before the use of invasive monitoring and intensive care units. The technique is associated with prolonged emergence and frequent dysphoria.

Although droperidol has been used as a neuroleptic for more than 4 decades, its ability to cause cardiac dysrhythmias has only recently been appreciated. Droperidol causes a dose-dependent prolongation of the QTc interval, and, in a subset of the population (of unknown incidence), this may lead to polymorphic ventricular tachycardia (torsade de pointes). Antiemetic doses of droperidol almost certainly are safe, but there is the possibility that larger, sedating doses may be associated with this dysrhythmia.94 In the United States, droperidol is labeled with a boxed warning that mandates continuous electrocardiographic monitoring for 2 to 3 hours after droperidol administration in doses above 2.5 mg; such doses are above those needed for a reliable antiemetic effect.

α2-Adrenoceptor Agonists

Clonidine was the first centrally acting α2-adrenergic agonist widely used in medicine. Introduced as an antihypertensive, a common adverse effect was sedation to which the patient became tolerant after 1 to 2 weeks of therapy. Because one person's adverse effect may be another person's therapeutic effect, clonidine was later investigated and used as a preoperative sedative (see Chapter 9). In some studies, such use was associated with diminished intraoperative requirements for hypnotic and analgesic medications and less intraoperative tachycardia and hypertension.

Dexmedetomidine is the first α2-adrenoceptor agonist specifically marketed as a sedative. It is considerably more selective for α2-adrenoceptors than clonidine. The primary site of its action as a sedative is in the locus ceruleus, where its effect is to mimic physiologic sleep.95 Dexmedetomidine decreases inhibitory neuronal outflow from the locus ceruleus to the ventrolateral preoptic nucleus, resulting in increased GABA release from the latter. In rats, dexmedetomidine produces analgesia at the spinal cord level by activating descending inhibitory pathways originating in the midbrain, thereby reducing pain impulses that would otherwise ascend in the cord. Additionally it acts synergistically with nitrous oxide to potentiate the latter's analgesic activity in the spinal cord.96

Dexmedetomidine produces intense sedation, although it cannot reliably produce amnesia, hypnosis, or general anesthesia.97 It does not have anticonvulsant properties. As would be expected, dexmedetomidine lowers blood pressure and heart rate, and dramatic decreases have occasionally occurred in patients without preexisting cardiovascular disease. Like clonidine, higher doses of dexmedetomidine can produce an initial increase in blood pressure that is believed to result from stimulation of α2B-adrenoceptors. Sympathetic stimulation is also responsible for the common side effect of dry mouth. In animals and humans, dexmedetomidine can markedly reduce the requirement for volatile or intravenous anesthetics and opioids. Sedative doses have very little effect on ventilation and do not appear to increase the ventilatory depressant effects of opioids.98

Dexmedetomidine is approved for sedation of mechanically ventilated adult patients, but only for up to 24 hours. The infusion typically is started near the end of an operative procedure before the patient is transported to the ICU or shortly after arrival. A bolus dose of 1 mcg/kg is given over 10 minutes, followed by an infusion of 0.003 to 0.012 mcg/kg/min. No ventilatory depression is associated with this sedation, and patients should require less opioid for management of postoperative pain. The heart rate usually is slow, although symptomatic bradycardia occasionally occurs, and dexmedetomidine should not be given to patients with preexisting heart block. Postoperative hypertension usually is well controlled; however, some patients experience hypotension and require pressor infusion, especially if they have preexisting ventricular dysfunction. Dexmedetomidine has also been evaluated for procedural sedation, and it was recently approved for this indication.99 Both clonidine and dexmedetomidine are able to suppress postoperative shivering, probably via stimulation of α2B receptors in the hypothalamus.

An intriguing possibility is that perioperative administration of an α2-adrenoceptor agonist decreases cardiovascular mortality. A meta-analysis concluded that such use decreases mortality and myocardial infarction after vascular surgery.100

Etomidate Derivatives

In order to take advantage of the desirable properties of etomidate without producing adrenal suppression, Cotten and colleagues have synthesized and evaluated 2 derivatives of etomidate that avoid adrenal suppression via 2 different mechanisms. The structures of methoxycarbonyletomidate (MOC-etomidate) and carboetomidate are shown in Fig. 41-6. Note that both are optically active. Thus far these novel compounds have been primarily evaluated in rats.

MOC-etomidate is an esterase-metabolized analogue of etomidate that, like other esterase-metabolized drugs, has a very short duration of action. When compared with etomidate in rats at equipotent doses, the duration of the loss of righting reflex was about 1 minute with MOC-etomidate and about 24 minutes with etomidate. Furthermore, there was no detectable adrenocortical suppression 30 minutes after administration.101

Carboetomidate is a simple but elegant analogue of etomidate in which 1 nitrogen atom of the imidazole ring is replaced with a carbon. It is this nitrogen atom in etomidate that binds to the heme iron atom of CYP11B, thereby preventing the binding of 11-deoxycortisol, the precursor to cortisol. Carboetomidate is approximately 3 orders of magnitude loss potent an inhibitor of CYP11B than is etomidate.102

Esterase-Metabolized Benzodiazepine (CNS 7056X)

CNS 7056X (Fig. 41-6) is an esterase-metabolized benzodiazepine. It is metabolized by nonspecific tissue esterases, as is remifentanil (see Chapter 42). The carboxylic acid metabolite that results from its hydrolysis is approximately 400 times less potent than the parent medication. The duration of the effect of CNS 7056X in sheep is less than that of midazolam after equisedating doses.103

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